CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

213433Orig1s000

PRODUCT QUALITY REVIEW(S)

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Reference ID: 4654387

EXECUTIVE SUMMARY

I. RECOMMENDATIONS AND CONCLUSION ON APPROVABILITY  The applicant of this 505(b)(2) new drug application has provided sufficient CMC information to assure the identity, purity, strength, and quality of the drug substance (clascoterone) and the drug product, WINLEVI® (clascoterone) Cream, 1%.

 Labels/labeling issues have been satisfactorily addressed.

 The Office of Process and Facility has made an overall “Acceptable” recommendation regarding the facilities involved in this NDA.

 The claim for categorical exclusion from the preparation of environmental assessment has been granted.

Therefore, from the OPQ perspective, this NDA is recommended for APPROVAL with expiration dating period of 36 months.

II. SUMMARY OF QUALITY ASSESSMENTS

A. Product Overview The applicant, Cassiopea SpA has submitted this 505(b)(1) new drug application for WINLEVI® (clascoterone) Cream, 1% for topical administration. WINLEVI® is indicated for the treatment of acne vulgaris in patients 12 years of age or older.

The active ingredient clascoterone is an androgen receptor inhibitor formulated as a white to almost white cream for topical dermatological use. Clascoterone is a white to almost white powder which is practically insoluble in water.

Each gram of cream of WINLEVI container 10 mg of clascoterone as the active ingredient and cetyl alcohol, mono and diglycerides, mineral oil, propylene glycol, vitamin E, edetate disodium, polysorbate 80, citric acid monohydrate, and purified water as the inactive ingredients.

WINLEVI cream is packaged and supplied as 60g in an epoxy-lined aluminum blind-end tube with a polypropylene cap. This product should be stored at 2ºC – 8ºC (38ºF – 46ºF) during shelf-life storage. Patients are instructed to store this drug product at room temperature 20ºC – 25ºC (68ºF – 78ºF) while in use. WINLEVI should be used within one month

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after opening. The unused product should be discarded 180 days after the date of dispensing.

WINLEVI cream is intended for topical administration to cleaned and dried affected skin area as uniform thin layer twice daily, in the morning and in the evening.

Proposed Treatment of acne vulgaris in patients 12 years of Indication(s) age or older including Intended Patient Population Duration of As prescribed Treatment Maximum Daily Dose As prescribed Alternative Methods N/A of Administration

B. Quality Assessment Overview

Drug Substance: Adequate The drug substance, clascoterone is an androgen receptor inhibitor with a good skin permeation. It binds weakly to the human androgen receptor, thus blocking the receptor and preventing downstream androgenetic gene activation. Clascoterone has been classified as a new molecular entity (NME) and is intended as the active ingredient of topical cream indicated for the treatment of acne vulgaris in patients 12 years of age or older.

Clascoterone is a white or almost white powder. It is practically insoluble in water, slightly soluble in ether, and very soluble in methanol and ethanol. It presents different polymorphic forms and the polymorphic form (b) (b) (4) identified as Form (4)shows a melting range of ºC. It also has the specific optical rotation of (b) (4) (b) (4)

Clascoterone (USAN) also identified throughout the application as Cortexolone-17α-propionate (INN) has the chemical name, [(8R,9S,10R,13S,14S,17R)-17-(2-hydroxyacetyl)-10,13-dimethyl-3-oxo­ 2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl] propanoate, a molecular formula of C24H34O5, a molecular weight of 402.5 g/mol, and the chemical structure below:

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Clascoterone is manufactured in accordance to current Good Manufacturing Practices (cGMP) requirements by (b) (4) and is packaged in (b) (4) . It is tested and release against a specification that assures the identity, strength, purity, and quality of the drug substance at release and throughout its (b) (b) (4) assigned retest date of (4) months when stored in a Information regarding the manufacture of clascoterone supplied by (b) (4) is provided in DMF (b) (4) . This DMF was reviewed by the Drug Substance Reviewer, Dr. Jeffrey Medwid on December 18, 2019 and was found to be adequate.

In summary, based on the review of the manufacturing information provided in DMF (b) (4) and the review of the additional information provided in the Drug Substance Module of this application, Dr. Medwid has concluded that the drug substance information provided is adequate to support approval of this application from the drug substance perspective. Dr. Medwid’s review is provided in the Drug Substance Chapter of the Integrated Quality Assessment (IQA).

Drug Product: Adequate WINLEVI® (clascoterone) Cream, 1% for topical administration has been developed for the treatment of acne vulgaris in patients 12 years of age or older. It is intended for twice a day topical application as uniform thin layer to cleaned dried affected skin area.

WINLEVI has been formulated as a white to almost white (b) (4) cream. Each gram of the cream contains 10mg (1%) clascoterone as the active ingredient and cetyl alcohol, mono and diglycerides, mineral oil, propylene glycol, vitamin E, edetate disodium, polysorbate 80, citric acid monohydrate, and purified water as inactive ingredients. Inactive ingredients used in the composition of the drug product are all compendial materials. Clascoterone was found to be (b) (4)

Therefore, the pH of final cream formulation was adjusted to (b) (4) for the Phase 3 studies. (b) (4) storage condition of 5ºC+ 3ºC was used and recommended as the shelf-life storage condition for the commercial drug product.

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WINLEVI cream is manufactured in accordance to cGMP requirements by Cassiopea SpA and is packaged as 60g in epoxy-lined blind-end aluminum tubes with polypropylene caps. The drug product is tested against a specification that assures the identity, strength, purity, and quality of the drug product at release and throughout its proposed shelf- life of 36 months. The applicant has provided sufficient stability data that supports the expiration dating period of 36 months for the drug product stored at 2ºC – 8ºC (38ºF – 46ºF). The applicant has also provided sufficient stability data that supports the storage of the drug product at room temperature, 20ºC – 25ºC (68ºF – 78ºF) while in use.

The drug product module of this application has been reviewed by the Drug Product Reviewer, Dr. Zhengfang Ge. Dr. Ge has concluded that the information provided in the drug product module is adequate to support the approval of this application from the drug product perspective. Dr. Ge’s review is provided in the Drug Product Chapter of the IQA.

Labeling: Adequate The CMC sections of the Prescribing Information (PI) as well as the immediate container and carton labels have been reviewed by the Drug Product Reviewer, Dr. Zhengfang Ge. Dr. Ge has found that the final PI as well as immediate container and carton labels submitted to the application have satisfactorily resolved all deficiencies noted in her Labeling Review #1, and therefore, she has recommended approval of this application from the CMC labeling/labels perspective.

Dr. Ge’s Labeling Review # 1 dated April 9, 2020 followed by her addendum to the Labeling Review # 1 dated July 13, 2020 noting her final recommendation of approval of PI labeling as well as container and carton labels from the CMC perspective are provided in the Labeling Chapter of the IQA.

Environmental Assessment: Adequate The applicant has requested a categorical exclusion from preparation of environmental assessment according to 21 CFR 25.31(b) based on the estimated introductory concentration of the active moiety into aquatic environment of (b) (4) µg/L which is less than 1ppb. The applicant has also provided the statement that to their knowledge, no extra ordinary circumstances exits per 21 CFR 25.31(d) and has provided supportive information for this statement.

Since the active ingredient of this new drug application is a new molecular entity and is an androgen receptor inhibitor, the acceptability of the request for the categorical exclusion has been reviewed by the

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Environmental Assessment Reviewer, Dr. Raanan Bloom. Dr. Bloom has found the applicant’s request for the categorical exclusion from preparation of environmental assessment adequate. Therefore, the categorical exclusion for this application is granted. Dr. Bloom’s review is provided in the Environmental Assessment Chapter of the IQA (right after the Labeling Chapter).

Manufacturing: Adequate Manufacturing Process: The manufacturing process for WINLEVI cream entails the preparations of (b) (4)

product specification.

The manufacturing process for WINLEVI cream has been reviewed by the OPMA Reviewer, Dr. Amit Kokate. Dr. Kokate has concluded that the proposed commercial manufacturing process is adequate.

Manufacturing Facilities: Based on the compliance profile, acceptable profile code, and experience in proposed manufacturing responsibilities, the drug substance manufacturing and testing sites have been recommended as acceptable. The drug product manufacturing site was originally recommended for preapproval inspection (PAI). Due to current travel restrictions associated with COVID-19 pandemic, in lieu of PAI, the acceptability of drug product manufacturing facility was determined based on the review of the facility and manufacturing documents and records that were submitted to the application per Agency’s request, in accordance to 704(a)(4).

Facilities involved in this application were also reviewed by the OPMA Reviewer Dr. Amit Kokate. Dr. Kokate has recommended that the overall facilities involved in this application as adequate.

Dr. Kokate review of the manufacturing process and facilities is provided in the Manufacturing Chapter of the IQA.

Biopharmaceutics: Adequate The biopharmaceutic review of this application was mainly focused on the adequacy of the proposed in-vitro release testing (IVRT) method, method

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validation, proposed IVRT acceptance criterion, and the review of comparative IVRT data from batches tested.

The proposed IVRT method, method validation, acceptance criteria, and IVRT results were reviewed and evaluated by the Biopharmaceutics Reviewer, Dr. Swapna Pamu. Dr. Pamu has found the proposed IVRT method and acceptance criteria adequate and supported by the data provided. In summary, Dr. Pamu has found the biopharmaceutics information provided adequate to support the approval of this application from the biopharmaceutics perspective. Dr. Pamu’s review is provided in Biopharmaceutics Chapter of the IQA.

Microbiology (if applicable): Adequate WINLEVI (clascoterone) Cream, is an (b) (4) , self-preserved, multi- dose nonsterile drug product for topical use.

Since the drug product is a self-preserved cream, one batch of finished drug product was tested for antimicrobial effectiveness (AET) and have shown to meet the requirements in USP <51>. As a nonsterile cutaneous drug product, WILEVI have shown to comply with the requirements in USP <1111> and the final drug product specification includes testing and acceptance criteria in accordance to USP <60>, USP <61>, and USP <62>.

The microbiology section of this application has been reviewed by the Microbiology Reviewer, Dr. Jason God. Dr. God has found the microbiology information and the updated drug product specification adequate to support the approval of this application from the microbiology perspective. Dr. God’s review is provided in Microbiology Chapter of the IQA.

C. Risk Assessment

From Initial Risk Identification Assessment

Factors that Initial Risk Lifecycle Attribute/ Final Risk can impact Risk Mitigation Considerations CQA Evaluation the CQA Ranking Approach / Comments (b) (4) Assay, (b) (4) M to H L None Degradation (Acceptable) Products, and Uniformity of Dosage Unit

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(b) (4)

D. List of Deficiencies for Complete Response

None

Application Technical: Hamid Shafiei, Ph.D. Branch IV/DNDP 2/ONDP/OPQ

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Hamid Digitally signed by Hamid Shafiei Shafiei Date: 8/10/2020 03:21:42PM GUID: 507d824300005f344cf8b5e5989f0057

QUALITY ASSESSMENT DATA SHEET IQA NDA Assessment Guide Reference

1. RELATED/SUPPORTING DOCUMENTS

A. DMFs: Date Item DMF # Type Holder Status Assessment Comments Referenced Completed (b) (4) (b) (4) II Adequate 10/06/2019 Reviewed by Jeffrey Medwid, Ph.D. III ------Sufficient information is provided in the NDA

B. OTHER DOCUMENTS: IND, RLD, RS, Approved NDA Document Application Number Description N/A N/A N/A

2. CONSULTS Discipline Status Recommendation Date Assessor Biostatistics N/A Pharmacology/Toxicology N/A CDRH-ODE N/A CDRH-OC N/A Clinical N/A Other N/A

40 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page

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Reference ID: 4654387

CHAPTER IV: LABELING IQA NDA Assessment Guide Reference

1.0 PRESCRIBING INFORMATION

Assessment of Product Quality Related Aspects of the Prescribing Information:

The Prescribing Information is deemed not ADEQUATE as proposed until it is revised satisfactorily to meet the regulatory requirements (See the List of Deficiencies at the end of this review).

1.1 HIGHLIGHTS OF PRESCRIBING INFORMATION

(b) (4)

Information Provided Item Assessor’s Comments in the NDA Product Title in Highlights Proprietary name WINLEVI Established name(s) (clascoterone) cream Adequate

Route(s) of administration topical Adequate Dosage Forms and Strengths Heading in Highlights Summary of the dosage form(s) Cream, 1 % Adequate and strength(s) in metric system.

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Assess if the tablet is scored. If N/A product meets guidelines and criteria for a scored tablet, state “functionally scored”

For injectable drug products for N/A parental administration, use appropriate package type term (e.g., single-dose, multiple-dose, single-patient-use). Other package terms include pharmacy bulk package and imaging bulk package.

1.2 FULL PRESCRIBING INFORMATION

1.2.1 Section 2 (DOSAGE AND ADMINISTRATION)

(b) (4)

Information Provided Item Assessor’s Comments in the NDA DOSAGE AND ADMINISTRATION section Special instructions for product (b) (4) twice Adequate preparation (e.g., reconstitution per day and resulting concentration, dilution, compatible diluents, storage conditions needed to maintain the stability of the reconstituted or diluted product)

1.2.2 Section 3 (DOSAGE FORMS AND STRENGTHS)

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Information Item Provided Assessor’s Comments in the NDA DOSAGE FORMS AND STRENGTHS section Available dosage form(s) cream Adequate Strength(s) in metric system 1%, each gram of cream Adequate contains 10 mg clascoterone If the active ingredient is a salt, apply the N/A USP Salt Policy per FDA Guidance A description of the identifying Not provided Not Adequate characteristics of the dosage forms, including shape, color, coating, scoring, - Add “white to almost and imprinting white cream” Assess if the tablet is scored. If product N/A meets guidelines and criteria for a scored tablet, state “functionally scored ” For injectable drug products for parental N/A administration, use appropriate labeling term (e.g., single-dose, multiple-dose, single-patient-use). Other package type terms include pharmacy bulk package and imaging bulk package.

1.2.3 Section 11 (DESCRIPTION)

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Information Provided Item Assessor’s Comments in the NDA DESCRIPTION section Proprietary and established Not Adequate name(s) WINLEVI cream - Change “WINLEVI cream” to “Winlevi (clascoterone) cream” … Dosage form(s) and route(s) of cream for topical dermatologicl Adequate administration use

If the active ingredient is a salt, N/A apply the USP Salt Policy and include the equivalency statement per FDA Guidance. List names of all inactive Each gram of WINLEVI Adequate ingredients. Use USP/NF names. cream 1% contains 10 mg of Avoid Brand names. clascoterone in a cream base of cetyl alcohol, citric acid monohydrate, edetate disodium, mineral oil, mono- and di-glycerides, polysorbate 80, propylene glycol, purified water, and vitamin E For parenteral injectable dosage N/A forms, include the name and quantities of all inactive ingredients. For ingredients added to adjust the pH or make isotonic, include the name and statement of effect. If alcohol is present, must provide N/A the amount of alcohol in terms of percent volume of absolute alcohol Statement of being sterile (if N/A applicable) Pharmacological/ androgen receptor inhibitor Adequate therapeutic class

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Chemical name, structural Chemically, clascoterone is Adequate formula, molecular weight cortexolone-17α propionate. The compound has the empirical formula C24H34O5 and molecular weight of 402.5 g/mol

If radioactive, statement of N/A important nuclear characteristics. Other important chemical or Not provided Not Adequate physical properties (such as pKa or pH) - Add “clascoterone is a white to almost white powder, practically insoluble in water”

Section 11 (DESCRIPTION) Continued Information Provided Item Assessor’s Comments in the NDA For oral prescription drug N/A products, include gluten statement if applicable Remove statements that may be N/A misleading or promotional (e.g., “synthesized and developed by Drug Company X,” “structurally unique molecular entity”

1.2.4 Section 16 (HOW SUPPLIED/STORAGE AND HANDLING)

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Information Provided Item Assessor’s Comments in the NDA HOW SUPPLIED/STORAGE AND HANDLING section Available dosage form(s) Cream Adequate Strength(s) in metric system 1% Adequate

Available units (e.g., bottles of 100 60-gram tube Adequate tablets) Identification of dosage forms, e.g., cream Adequate shape, color, coating, scoring, imprinting, NDC number Assess if the tablet is scored. If N/A product meets guidelines and criteria for a scored tablet, state “functionally scored” For injectable drug products for N/A Adequate parental administration, use appropriate package type term (e.g., single-dose, multiple-dose, single-patient-use). Other package terms include pharmacy bulk package and imaging bulk package. Special handling about the Do not freeze. The product Adequate supplied product (e.g., protect should be used in 1 month from light, refrigerate). If there is a statement to “Dispense in original container,” provide reason why (e.g. to protect from light or moisture, to maintain stability, etc.) If the product contains a N/A desiccant, ensure the size and shape differ from the dosage form and desiccant has a warning such as “Do not eat.” Storage conditions. Where Prior to Dispensing: Store Adequate applicable, use USP storage range the product in a refrigerator OPQ-XOPQ-TEM-0001v06 Page 6 Effective Date: February 1, 2019

rather than storage at a single between 36°F and 46°F temperature. (2°C and 8°C). Do not freeze.

Dispensing Instructions for the Pharmacist: Direct the patient to store the product while in use at room temperature up to 77°F (25°C). Do not freeze. The product should be used within 1 month after opening.

Latex: If product does not N/A contain latex and manufacturing of product and container did not include use of natural rubber latex or synthetic derivatives of natural rubber latex, state: “Not made with natural rubber latex. Avoid statements such as “latex-free.” Include information about child- N/A resistant packaging

1.2.5 Other Sections of Labeling N/A

1.2.6 Manufacturing Information After Section 17 (for drug products) Information Provided in Item Assessor’s Comments the NDA Manufacturing Information After Section 17 Name and location of Adequate business (street address, city, state and zip code) of the manufacturer, distributor, and/or packer

2.0 PATIENT LABELING

The following CMC information is provided in the Patient Labeling and is adequate

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Important Information: WINLEVI cream is for use on the skin only (topical). Do not use WINLEVI cream in or on your mouth, eyes, or vagina.

How should I store WINLEVI cream?

Store WINLEVI cream at room temperature, (b) (4)

Keep WINLEVI cream and all medicines out of the reach of children.

What are the ingredients in WINLEVI cream?

Active ingredient: clascoterone Inactive ingredients: cetyl alcohol, citric acid monohydrate, edetate disodium, mineral oil, mono- and di-glycerides, polysorbate 80, propylene glycol, purified water, and vitamin E

Evaluation:

The How Should I store WINLEVI cream Section should be revised to the following:

Store the product while in use at room temperature up to 77°F (25°C). Discard the unused product 1 month after opening.

3.0 CARTON AND CONTAINER LABELING

3.1 Container Label

3 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page

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Assessor’s Comments Item Information Provided in the NDA about Carton Labeling Proprietary name, established Winlevi Not Adequate name, and dosage form (font size clascoterone cream 1% Established name and prominence clascoterone should be with separate strength from the established name. -change to Winlevi (clascoterone) cream 1% Dosage strength 1% Adequate

Route of administration For topical use only Adequate Not for ophthalmic, oral or vaginal use If the active ingredient is a salt, N/A include the equivalency statement per FDA Guidance Net contents (e.g. tablet count) 60-gram Adequate “Rx only” displayed on the Provided Adequate principal display NDC number Provided Adequate Lot number and expiration date Provided Not Adequate

Add lot number and expiration date on carton label Storage conditions. If applicable, On Labels for Container and Carton: Not Adequate include a space on the carton Store WINLEVI cream 1% while in labeling for the user to write the use at room temperature up to 77°F The storage condition on new BUD. (25°C). Do not freeze. The product the label of the shipping should be used within 1 month after cases is adequate. opening. However, the storage On Shipping Cases (b) (4) condition on the container Labels: and carton labels should be Store the product in a refrigerator changed to the following: between 36°F and 46°F (2°C and 8°C). Do not freeze. Store the product while in use at room temperature up to 77°F (25°C). Discard the unused product 180 days after the date of dispensing. The product should be used within 1 month after opening.

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For injectable drug products for N/A Adequate parental administration, use appropriate package type term (e.g., single-dose, multiple-dose, single-patient-use) Other package terms include Adequate pharmacy bulk package and imaging bulk package which require “Not for direct infusion” statement. If alcohol is present, must N/A provide the amount of alcohol in terms of percent volume of absolute alcohol Bar code Provided Adequate

Assessor’s Information Provided in the Item Comments about NDA Carton Labeling Name of manufacturer/distributor Provided Adequate

Medication Guide (if applicable) Provided Adequate

No text on Ferrule and Cap N/A overseal When a drug product differs N/A from the relevant USP standard of strength, quality, or purity, as determined by the application of the tests, procedures, and acceptance criteria set forth in the relevant compendium, its difference shall be plainly stated on its label. And others, if space is available Usual dose, and Keep out of reach of Adequate children, are provided in carton label.

Assessment of Carton and Container Labeling: Inadequate

 The established name should be in parenthesis. The title of the drug product on the labels should be displayed as follows:

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Winlevi (clascoterone) cream 1%

 The storage condition on the carton/container labels should be changed to the following:

Storage: Must be refrigerated, store at 2°C to 8°C (36°F to 46°F) until dispensed to the patient. Once dispensed, patient is to store WINLEVI Cream 1% at room temperature up to 77°F (25°C) for 1 month. Do not freeze. Discard the unused portion 1 month after first opening.

ITEMS FOR ADDITIONAL ASSESSMENT List of Deficiencies

A. For Prescribing Information:

Section 3 Dosage Forms and Strengths  Add “white to almost white cream” to

Section 11 Description

 Change the 1st sentence to Winlevi (clascoterone)…  Add “white to almost white cream” for the active ingredient

Section 16: How Supplied

Change the storage condition to the following

 Prior to Dispensing: Store the product in a refrigerator between 36°F and 46°F (2°C and 8°C). Do not freeze.

 Dispensing Instructions for the Pharmacist: Direct the patient to store the product while in use at room temperature up to 77°F (25°C). The product should be used within 1 month after opening.

B. For Patient Instruction:

Revise “The How Should I store WINLEVI cream” to the following:

Store the product while in use at room temperature up to 77°F (25°C). The product should be used within 1 month after opening.

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C. For Container/Carton Labels:

 The established name should be in parenthesis. The title of the drug product on the labels should be displayed as follows with a separate line for strength:

Winlevi (clascoterone) cream 1%

 The storage condition on the carton/container labels should be changed to the following:

Storage: Must be refrigerated, store at 2°C to 8°C (36°F to 46°F) until dispensed to the patient. Once dispensed, patient is to store WINLEVI Cream 1% at room temperature up to 77°F (25°C) for 1 month. Do not freeze. Discard the unused portion 1 month after first opening.

Overall Assessment and Recommendation: The NDA is not ready for approval in its present form per CFR 314.125(b)(6) until the outstanding labeling issues listed in the List of Deficiencies are satisfactorily resolved.

Primary Labeling Assessor Name and Date:

Zhengfang Ge, Ph. D. Reviewer, BRANCH IV/DIVISION II OFFICE OF NEW DRUG PRODUCT

Secondary Assessor Name and Date (and Secondary Summary, as needed):

I agree with Dr. Ge’s assessment on the labeling as well as labels, and therefore, I concur with her recommendation that this application is not ready for approval in its present from the CMC labeling perspective until the deficiencies delineated in the List of Deficiencies are satisfactorily resolved.

Moo-Jhong Rhee, Ph. D. Branch Chief, BRANCH IV/DIVISION II OFFICE OF NEW DRUG PRODUCT

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Zhengfang Digitally signed by Zhengfang Ge Ge Date: 4/09/2020 03:45:31PM GUID: 508da7210002a030e76df4f60ccd142a

Moo Jhong Digitally signed by Moo Jhong Rhee Rhee Date: 4/09/2020 04:01:33PM GUID: 502d0913000029f9798ca689a802fa55 Memorandum DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH

Date: July 10, 2020

From: Zhengfang Ge, Ph.D. ONDP/Division II/Branch IV

Through: Wendy Wilson, Ph.D. Director, ONDP/Division II

To: Labeling Review of NDA 213433: Winlevi (clascoterone) cream

Subject: Final Recommendation for Labeling/Labels

The labeling review #1 has noted the following issues:

For Prescribing Information:

Section 3 Dosage Forms and Strengths  Add “white to almost white cream”

Section 11 Description

 Change the 1st sentence to Winlevi (clascoterone)…  Add “white to almost white cream” for the active ingredient

Section 16: How Supplied

Change the storage condition to the following  Prior to Dispensing: Store the product in a refrigerator between 36°F and 46°F (2°C and 8°C). Do not freeze.

 Dispensing Instructions for the Pharmacist: Direct the patient to store the product while in use at room temperature up to 77°F (25°C). The product should be used within 1 month after opening.

For Patient Instruction:

 Revise “The How Should I store WINLEVI cream” to the following:

 Store the product while in use at room temperature up to 77°F (25°C). The product should be used within 1 month after opening.

For Container/Carton Labels:

 The established name should be in parenthesis. The title of the drug product on the labels should be displayed as follows with a separate line for strength:

Winlevi (clascoterone) cream 1%

 The storage condition on the carton/container labels should be changed to the following:

Storage: Must be refrigerated, store at 36°F to 46°F (2°C to 8°C) until dispensed to the patient. Once dispensed, patient is to store WINLEVI Cream 1% at room temperature up to 77°F (25°C) for 1 month. Do not freeze. Discard the unused portion 1 month after first opening.

The above CMC requests along with the DMEPA’s requests have been implemented in the revised labeling. The storage condition has been revised to the following language which is supported by the stability data.

Prior to Dispensing: Store the product in a refrigerator between 36°F and 46°F (2°C and 8°C). Do not freeze.

Dispensing Instructions for the Pharmacist: Direct the patient to store the product while in use at room temperature, between 68°F and 77°F (20°C to 25°C). Do not freeze. Discard the unused product 180 days after the date of dispensing or 1 month after first opening, whichever is sooner.

The revised container/carton labels are satisfactory and provided in the Attachment.

Recommendation:

This NDA is now recommended for Approval from the labeling perspective.

2 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page Zhengfang Digitally signed by Zhengfang Ge Ge Date: 7/13/2020 01:33:44PM GUID: 508da7210002a030e76df4f60ccd142a

Wendy Digitally signed by Wendy Wilson- Lee Wilson- Lee Date: 7/13/2020 01:36:44PM GUID: 50816dbc000085595ca3284bbca465a8

CHAPTER III: ENVIRONMENTAL IQA NDA Assessment Guide Reference

NDA-213433-ORIG

R REGIONAL INFORMATION

Environmental Analysis

Assessment: Adequate

The submitted categorical exclusion is appropriate for the estimated amount of clascoterone to be used for the requested indication. A supported statement of ‘no extraordinary circumstances’ has been submitted. The claim of categorical exclusion is adequate.

Applicant’s Position: The applicant submitted a claim for categorical exclusion (EDR Section 1.12.14) under 21 Code of Federal Regulations (CFR) Section 25.31 on the basis that the estimated introductory concentration (EIC) of the active moiety (clascoterone) into the aquatic environment is less than 1 part per billion (ppb) or µg/L. The applicant states that, to their knowledge, no extraordinary circumstances exist under 21 CFR Section 25.15(d) that would warrant preparation of an EA. In a revised claim, the applicant provides a recalculated EIC and supporting information for the ‘no extraordinary circumstances’ statement.

FDA Assessment: The initial claim for exclusion submitted with the original application estimated the EIC based on drug product and not, as required, on the estimated Kg of drug substance sold in the U.S. An IR was sent on 11/01/2019, advising the applicant to recalculate the EIC based on ‘Kg drug substance sold’ and to address the androgen receptor activity of the drug as related to aquatic toxicity. A link to the FDA Guidance for drugs with estrogenic, androgenic, or thyroid activity in the environment was provided.

The applicant submitted a revised claim for exclusion using Kg drug substance sold/yr estimates from 2020 to 2025 to provide a 5th year EIC of (b) (4) µg/L. This is a conservative estimate. The calculation assumes that all drug substance sold in the U.S./year is used, flows directly into publicly owned treatment works and discharged as effluent with no loss due to the product’s topical administration, metabolism, (bio) degradation, or dilution. This EIC calculation meets the exclusion available at 21 CFR 25.31(b).

In support of the ‘no extraordinary circumstances’ statement, the applicant uses a “read across” analysis comparing clascoterone to other antiandrogen compounds, including progesterone, flutamide, finasteride, and cyproterone acetate. Of the compounds, comparison to flutamide appears most appropriate since flutamide has been tested in a variety of fish models (see

OPQ-XOPQ-TEM-0001v06 Page 1 Effective Date: February 1, 2019

references in EDR Section 1.12.14). At water concentrations of 412 μg/L, flutamide elicited only minor phenotypic alterations in flathead minnow. At higher concentrations (651 – 1000 μg/L), significant effects were observed in mekada and at 1700 μg/L in zebrafish. At concentrations between 10 and 50 μg/L, there were only small changes in the spiggin secretion in stickleback fish, an androgen-dependent function. Comparison of clascoterone EICs to flutamide water concentrations that elicit responses in exposed fish, provide a sufficient margin of safety for the effects of clascoterone in the aquatic environment.

We note that by year 2022, the amount of clascoterone estimated to be sold increases significantly, with a concurrent increase in EIC. For future claims of categorical exclusion, the EA team may request the applicant to review the literature and, if warranted, conduct chronic fish toxicity studies, including androgen receptor inhibition, at these higher EICs values.

Primary Environmental Assessor Name and Date:

Raanan Bloom, Ph.D.; 4/7/2020

Secondary Assessor Name and Date:

Scott Furness, Ph.D.;

OPQ-XOPQ-TEM-0001v06 Page 2 Effective Date: February 1, 2019

Raanan Digitally signed by Raanan Bloom Bloom Date: 4/07/2020 12:28:18PM GUID: 508da72a0002a6d1071f3297897e4f1f

Michael Digitally signed by Michael Furness Furness Date: 4/07/2020 04:06:55PM GUID: 502e8c7600003dd8331cf6eebf43697a

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BIOPHARMACEUTICS

Product Background: NDA: 213433 Drug Product Name / Strength: Clascoterone Cream 1% Route of Administration: Topical Applicant Name: Cassiopea SpA Indication: Treatment of Acne vulgaris in patients 9 years of age and older.

Review Summary: Adequate

The proposed product, Clascoterone Cream 1% is indicated for the treatment of Acne vulgaris in patients 9 years of age and older, and is intended for topical use only. Application was submitted through 505(b)(1) pathway on 08/19/2019.

Biopharmaceutics assessment focuses on the evaluation of IVRT method development, validation, comparative IVRT data and in vitro release acceptance criteria.

Upon review of in vitro release data, the proposed IVRT method is adequate. Based on the submitted IVRT data, proposed IVRT acceptance criteria is acceptable. The approved in vitro release method and acceptance criteria are stated below:

Receptor Sampling Sampling Acceptance Apparatus Membrane RPM Temp fluid volume Times criterion PermeGear vertical glass Whatman diffusion jacketed cells plain nylon with orifice diameter 6% Brij 0.2micron 1, 2, 3, 5 (b) (4) 11.28mm, receptor C20 in 500+/­ 32℃ membrane 200 and 7 chamber capacity of 8 0.9% 50 μL µg/cm2/hr1/2 filter, 25 +/- 1℃ hours mL and internal diameter NaCl mm of 30 mm and diffusion diameter area of 1.00 cm2

From the Biopharmaceutics perspective NDA-213433 for Clascoterone Cream 1% is adequate.

List Submissions being reviewed (table): SUBMISSION(S) REVIEWED DOCUMENT DATE Application 213433 - Sequence 0001 - 0001 (1) 08/19/2019 ORIG-1 /New/NDA 08/19/2019 Application 213433 - Sequence 0016 - 0016 (16) 01/10/2020 ORIG-1 /Quality/Response To Information Request 01/10/2020 Application 213433 - Sequence 0015 - 0015 (15) 01/10/2020 ORIG-1 /Quality/Response To Information Request 01/10/2020 Application 213433 - Sequence 0014 - 0014 (14) 12/27/2019 ORIG-1 /Quality/Response To Information Request 12/27/2019 Application 213433 - Sequence 0012 - 0012 (12) 12/02/2019 ORIG-1 /Quality/Response To Information Request 12/02/2019

Highlight Key Outstanding Issues from Last Cycle: None.

QUALITY ASSESSMENT

Concise Description Outstanding Issues Remaining: N/A

BCS Designation: Reviewer’s Assessment: Not reported.

Solubility: Cortexolone-17α-propionate is practically insoluble in water, slightly soluble in ether and very soluble in alcohols like methanol and ethanol.

Permeability: Not reported.

Ta ble 1: Formulation composition

(b) (4) (b) (4)

(b) (4)

(b) (4) (b) (4)

(b) (4)

In vitro release method Information Request 1 dated 11/1/2019:

Applicant was asked to develop and validate the IVRT method and propose in vitro release acceptance criteria (range) for the proposed drug product to be used systemically at release and during stability as a quality control parameter.

Applicant’s response1, 2 In response to the above deficiency the Applicant developed an In Vitro Release Test (IVRT) with Franz-cell to indirectly evaluate the physiochemical characteristics of the cream and the product performance of industrial batches and also to verify the effects that the minor changes applied to the manufacturing process over time could have had on the product performance.

(b) (4)

1 Application 213433 - Sequence 0012 - Quality information amendment 2 Application 213433 - Sequence 0014 - Quality information amendment QUALITY ASSESSMENT

Reviewer’s comments: (b) (4)

Therefore, in reviewer’s opinion selection of medium, membrane and sampling time points are justified and acceptable in IVRT method. Please see appendix for additional details.

The final IVRT Method parameters are provided below

QUALITY ASSESSMENT

IVRT method validation: The applicant submitted an IVRT method validation report # 19-1-06 for its Cortexolone 17a­ propionate Cream 1% in Sequence 14, Module 3.2.P.5.3.

The IVRT method was validated for its specificity, selectivity, linearity, range, accuracy (% recovery), precision (system precision, method precision, intermediate precision), robustness and solution stability. The reviewer checked the method validation report and noted that all the method validation parameters met their acceptance criteria. The validation work foresaw the execution of a Franz cell test on six cells for each of the following products:

Process validation batches at standard potency: - Cortexolone 17α-propionate 1% cream batch LL076 - Cortexolone 17α-propionate 1% cream batch LL139 - Cortexolone 17α-propionate 1% cream batch LL209

Batch at altered (lower and higher) potency: - Cortexolone 17α-propionate 0.5% cream batch 7471/1 - Cortexolone 17α-propionate 1.5% cream batch 7472/1

In specificity experiment, release rate from altered batches (0.5% and 1.5%) were compared to validation batch (1%). Pairwise comparisons fell outside the limits of 75.00% and 133.33%.

Based on the release rate, IVRT method is considered to be sensitive to detect the differences in release rate.

All the results obtained during the validation work of the method for the evaluation of Cortexolone 17α-propionate 1% cream release by Franz cell test comply with the acceptance criteria.

The IVRT method was demonstrated to be specific, linear, accurate, precise and robust.

Applicant submitted the analytical method validation report #11-1-12 in Module 3.2.P.5.3 for the assay of cortexolone3 which will be evaluated by drug product reviewer.

3 Application 213433 - Sequence 0014 - Validation of Analytical Procedures QUALITY ASSESSMENT

Reviewer’s assessment:

To characterize the linearity, precision and reproducibility of the IVRT method, three IVRT runs were conducted, each with a set of 6 cells, on three different days with the validation batches. The linearity of the release rate (slope) was calculated across the range of sampling times for within and across runs and R2 is NLT 0.98.

For accuracy determination two batches were used and compared pairwise. The 90% confidence interval for each pairwise comparison results are within the limits of 75.00% and 133.33%. Precision and reproducibility experiments variability in release rates are within 15%

For sensitivity, specificity and selectivity experiments two intentionally altered (0.5% and 1.5% potency) batches were compared with validation batch. Pairwise comparisons fell outside the limits of 75.00% and 133.33%. Based on the release rate, IVRT method is sensitive to detect the differences in release rate.

Therefore, in reviewer’s opinion IVRT method was demonstrated to be specific, linear, accurate, precise and robust (Please see appendix for more details).

Method validation data are adequate.

(b) (4)

4 Application 213433 - Sequence 0015 - Quality information amendment

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(b) (4)

Reviewer also calculated and verified the above results and these are in agreement with the results provided by the applicant. The in vitro release test result indicate that the drug product release rate is similar over time.

In Vitro Drug Release Study to support the process change6 The in vitro release test was used to evaluate if the minor changes (b) (4) applied to the manufacturing process of engineering and validation batches, after the manufacturing of the pivotal phase III clinical batch 6800/1, might have had any impact on the physiochemical characteristics of the drug product and its performance. To do this, results of the in vitro release test performed on samples of clinical batch 6800/1, were compared with results obtained with the 3 validation batches (LL076, LL139 and LL209). The results indicate that the release rate in all batches are comparable.

Comparative IVRT data for Phase 3 batch (6800/1) and registration batches:

(b) (4)

Results were analyzed as described in USP <1724>, considering batch 6800/1 as the reference (R) and batches LL076, LL139 and LL209 as test batch (T); T/R slope ratios were evaluated to get the 90% confidence intervals to see if these fall within the 75% to 133.33% .

6 Application 213433 - Sequence 0012 - Drug Product (CB-03-01Cream 1%) QUALITY ASSESSMENT

Reviewer’s comment: Reviewer also calculated and verified the above results and these are in agreement with the results provided by the applicant.

In vitro release acceptance criteria: Applicant proposed IVRT specification of (b) (4) µg/cm2/hr1/2 for release and shelf life. Based on the submitted data obtained from the Phase 3 batch and all the registration batches, applicant’s proposed specification is acceptable.

List of Deficiencies: None

Primary Biopharmaceutics Reviewer Name and Date: Swapna Pamu, MS

Secondary Reviewer Name and Date (and Secondary Summary, as needed): Vidula Kolhatkar, Ph.D.

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APPROVED BY:

Primary Biopharmaceutics Reviewer: Swapna Pamu, MS

Secondary Biopharmaceutics Reviewer Vidula Kolhatkar, Ph.D.

Vidula Digitally signed by Vidula Kolhatkar Kolhatkar Date: 4/07/2020 01:05:44PM GUID: 5424aeae00c3274f93e50573f7ca407e

Swapna Digitally signed by Swapna Pamu Pamu Date: 4/07/2020 12:38:55PM GUID: 5ab948e8002c8e63080fe7187098154c CHAPTER VII: MICROBIOLOGY

Product Information Non-sterile, topical cream indicated for treatment of acne vulgaris NDA Number 213433 Assessment Cycle Number 1 Drug Product Name/ Strength Winlevi (clascoterone) / 1% Route of Administration Topical Applicant Name Cassiopea SpA Therapeutic Classification/ OND Division Manufacturing Site Cosmo SpA Via C. Colombo, 1 Lainate, Milan, Italy 20020 Method of Sterilization N/A – drug product is non-sterile

Assessment Recommendation: Adequate

Assessment Summary: This review covers the microbiological quality of the non-sterile drug product.

List Submissions being assessed (table): Document(s) Assessed Date Received eCTD seq 0001 08/19/2019 eCTD seq 0015 01/10/2020 eCTD seq 0020 02/21/2020 eCTD seq 0022 03/27/2020 eCTD seq 0025 05/08/2020

Highlight Key Issues from Last Cycle and Their Resolution: (None)

Remarks: Drug product is (b) (4) , self-preserved, multi-use, topical cream.

Concise Description of Outstanding Issues (List bullet points with key information and update as needed): (None)

Supporting Documents: (None)

S DRUG SUBSTANCE Drug substance is supplied non-sterile.

Assessment: Adequate OPQ-XOPQ-TEM-0001v06 Page 1 Effective Date: February 1, 2019

P.1 DESCRIPTION OF THE COMPOSITION OF THE DRUG PRODUCT  Description of drug product – Non-sterile, white to almost white homogenous cream.

 Drug product composition –

Table 1: Composition of clascoterone 1%

(b) (4)

Table 1 was reproduced from Table 1 in “Description and Composition of the Drug Product (CB-03­ 01, Cream 1%),” located in Module 3.2.P.1

 Description of container closure system – Epoxy-lined, 60g aluminum tube with polypropylene closure. A 10g tube of the same composition is used for physician samples.

P.2 PHARMACEUTICAL DEVELOPMENT P.2.5 MICROBIOLOGICAL ATTRIBUTES (b) (4)

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Reference ID: 4654387